Tumor immunology has come into the limelight since the realization that antitumor cytotoxic T lymphocytes (CTLs), which constitute the major effectors involved in tumor rejection, can be cultured in vitro and used as tools to identify the target antigens expressed by the tumor cells (Boon et al. 1994). Tumor-specific CTLs have been found in most mouse tumor models, and in several human tumor types, mainly in melanoma. By using a genetic approach based on the transfection of genomic or cDNA libraries, we cloned the genes encoding a number of melanoma antigens. This led to the molecular identification of these antigens which usually consist of a peptide derived from an intracellular protein and presented to CTLs by an HLA class I molecule. On the basis of their pattern of expression, these antigens can be classified into three groups. Antigens of the first group are encoded by genes that are expressed in the tumor cells but are silent in normal adult tissues except the testis. The second group consists of differentiation antigens that are expressed in melanoma and in normal melanocytes. Antigens of the third group are unique to individual tumors and appear through tumor-specific mutations in genes expressed ubiquitously.